title: Adenylate cyclase toxin promotes internalisation of integrins and raft components and decreases macrophage adhesion capacity.
abstract: Bordetella pertussis, the bacterium that causes whooping cough, secretes an adenylate cyclase toxin (ACT) that must be post-translationally palmitoylated in the bacterium cytosol to be active. The toxin targets phagocytes expressing the CD11b/CD18 integrin receptor. It delivers a catalytic adenylate cyclase domain into the target cell cytosol producing a rapid increase of intracellular cAMP concentration that suppresses bactericidal functions of the phagocyte. ACT also induces calcium fluxes into target cells. Biochemical, biophysical and cell biology approaches have been applied here to show evidence that ACT and integrin molecules, along with other raft components, are rapidly internalized by the macrophages in a toxin-induced calcium rise-dependent process. The toxin-triggered internalisation events occur through two different routes of entry, chlorpromazine-sensitive receptor-mediated endocytosis and clathrin-independent internalisation, maybe acting in parallel. ACT locates into raft-like domains, and is internalised, also in cells devoid of receptor. Altogether our results suggest that adenylate cyclase toxin, and maybe other homologous pathogenic toxins from the RTX (Repeats in Toxin) family to which ACT belongs, may be endowed with an intrinsic capacity to, directly and efficiently, insert into raft-like domains, promoting there its multiple activities. One direct consequence of the integrin removal from the cell surface of the macrophages is the hampering of their adhesion ability, a fundamental property in the immune response of the leukocytes that could be instrumental in the pathogenesis of Bordetella pertussis.
authors.affiliation: Unidad de Biofísica and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Martín
authors.forename: Kepa B
authors.initials: KB
authors.lastname: Uribe
authors.forename: Geraxane
authors.initials: G
authors.lastname: Gómez-Bilbao
authors.forename: Helena
authors.initials: H
authors.lastname: Ostolaza
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D016023:Integrins / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D021381:Protein Transport / Q000187:drug effects
chemical_list: D037361:Adenylate Cyclase Toxin; D016023:Integrins; D008565:Membrane Proteins